This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08- AG-101: Genetic factors affecting rates of change in disease risk factors with age. Alzheimer's disease (AD) is the most critical unmet need in neurological medicine because there are no disease- modifying therapies that improve the dementia or cognitive decline associated with it. Over 5 million Americans suffer from AD and unless effective therapies for preventing or delaying its onset are developed, it is estimated that more than 16 million Americans will suffer from AD by 2050. The science described in this grant application has the real potential of being transformational to clearly identify specific genetic factors that affect the rate of development of AD and to identify preventive therapies and approaches for healthier aging. The general relationship between APOE genotype and the age of onset for AD is well-documented since 1993. Recent preliminary results show that age of onset of AD is a function of at least two pathogenesis specific genes APOE and TOMM40, each with multiple determinants that affect their protein-protein interactions, residing on the same linkage disequilibrium (LD) region. This proposal develops and tests the paradigm that specific variants are cis- linked to APOE [unreadable]3 and are associated with changes in the age of onset distribution for Alzheimer's disease (AD). The most significant variants of TOMM40 have evolved on the backbone or cis to APOE [unreadable]3 LD region, and not cis to the APOE [unreadable]4 LD region. The TOMM40 gene, which codes for the translocase of the outer mitochondrial membrane, interacts with APOE proteins, modified by the configuration of TOMM40 and the specific APOE isoform. As a consequence of these findings, an AD prevention trial is planned to validate the predictive accuracy of the genetically-based diagnostic and to test a specific preventive drug. Development of disease risk with age may be a function of many small genetic and environmental factors. The proposed approach provides a novel framework for genetic analysis of complex diseases that involve multiple small signals from several interacting genes and is well-aligned with the availability of deep-sequencing data and with phenotypic data available from long-term longitudinal studies available in the public domain. Changes in mitochondrial function are associated with many diseases of aging: by clearly elucidating genetic variants in TOMM40 associated with age-related disease risk, interventions will be identified to delay the onset of AD. Completion of the program will greatly augment the evidence base for the genetic factors that influence the development of AD with age, test approaches for AD prevention and provide powerful bioinformatic tools to study other clinically-relevant diseases in the context of age-related risk. Alzheimer's disease is a critical unmet medical need because there are no disease-modifying therapies that improve the dementia or cognitive decline associated with it. Over 5 million Americans suffer from AD at a cost of $91 billion annually to Medicare alone. Our studies build on a new genetics discovery to understand genetic factors affecting the rate of change in disease risk for AD with age that will lead to the discovery of preventive therapies for Alzheimer's disease.